Nicotine dependence occurs in approximately 50 percent of daily smokers but the biology of the predisposition to nicotine dependence is unknown. Dopamine has been repeatedly found to play a central role in the reinforcing actions of numerous addicting drugs and may thus be an important determinant of addiction. Systemic administration of nicotine results in increased extracellular dopamine levels within the mesolimbic dopamine system that parallel those seen in cocaine and amphetamine administration. Furthermore, in animals the magnitude of the nicotine-induced changes in dopaminergic neurotransmission correlates with the rate of development of addiction behavior. This R21 project will test the use of positron emission tomography (PET) to measure the amount of dopamine released in the ventral striatum/nucleus accumbens after a nicotine challenge in cigarette smokers that are dependent on nicotine. Sensitivity to nicotine-induced dopamine release will be optimized by the use of 3D PET acquisition, higher raclopride dose (0.2 mCi / kg) and selective regions-of-interest for the mesolimbic system (predominantly the nucleus accumbens) drawn on high-resolution magnetic resonance images. We propose to study 30 daily smokers that demonstrate nicotine dependence (greater than 4 on the Fagerstom scale) using Li IC]raclopride PET and high resolution MRI. Each subject will undergo raclopride PET before and during a pharmacologic challenge. Ten subjects will receive placebo, ten subjects will receive 25 ug/kg i.v. and ten subjects will receive 50 ug/kg i.v. We will examine the hypotheses that systemic nicotine administration releases dopamine in the nucleus accumbens and that the amount of dopamine released is dependent on the plasma levels of nicotine achieved during the challenge. If completed, this R21 will demonstrate the utility of evaluating the mesolimbic dopamine release during nicotine exposure in smokers. We plan to use this information to design a subsequent project to investigate the biological differences between smokers who are not addicted and those smokers who are addicted. Ultimately, this information may lead to a better understanding of biological predispositions to nicotine dependence and potential treatment approaches for smoking cessation.